Erythropoietin promotes the erythroid differentiation of hematopoietic stem cells that reside within the local niche environment in the bone marrow. Erythropoietin promotes erythroid progenitor cell survival, proliferation and differentiation to mature red blood cells. A two phase culture system of human CD34+ hematopoietic progenitor cells with erythropoietin stimulated erythroid differentiation during the second phase demonstrates the sensitivity of erythropoiesis to stress conditions of low erythropoietin and low oxygen tension, and vasopressin contributions to erythropoiesis. While the potential for erythropoietin supplementation with hydroxyurea to increase fetal hemoglobin has been suggested for sickle cell patients, we found that increasing erythropoietin or its receptor in erythroid differentiating CD34+ cell cultures increased proliferation and hemoglobin positive cells without increasing fetal hemoglobin, indicating that increased erythropoietin signaling increases erythrocyte production but alone is insufficient to alter the hemoglobin program to increase fetal hemoglobin. However, in addition to increasing the erythroid mass and increasing the capacity for oxygen delivery, erythropoietin also improves glucose utilization. The bone marrow microenvironment has the potential to influence erythropoiesis and erythropoietin can also affect the bone marrow microenvironment to decrease bone marrow adipocytes and affect bone remodeling. The potential contribution of erythropoietin in maintaining the bone marrow microenvironment will be further investigated. We found that erythropoietin exhibits an anti-inflammatory response associated with diet-induced obesity. Conversely, inflammation can adversely affect erythropoietin stimulated erythropoietic response. However, increase plasma levels of pro-inflammatory cytokine IL-6 is observed in polycythemia vera with excess red blood cell production not to elevated erythropoietin production. Polycythemia vera is predominantly an acquired clonal stem cell disease associated with the somatic JAK2V617F mutation that is able to activate erythropoietin receptor signaling pathways including STAT3. We observed that IL-6 activated STAT3 signaling in granulocytes of polycythemia vera patients which was abrogated by treatment with JAK1/2 inhibitor. Also, IL-6 activated AKT signaling in granulocytes of polycythemia vera patients and in human erythroleukemia HEL cells with homozygous expression of mutant JAK2V617F, which was blocked by treatment with JAK2 inhibitor. IL-6 activation of STAT3 and AKT appears to be dependent on the specific myeloproliferative neoplasms and is not observed in granulocytes from patients with essential thrombocythemia where IL-6 inhibited STAT3 and AKT activity that was blocked by JAK1/2 inhibitor in JAK2V617F positive granulocytes and enhanced in JAK2V617F negative granulocytes. These differential responses to IL-6 and inhibitors of JAK1/2 and JAK2 depend on the specific myeloproliferative neoplasms. In addition, in contrast to inhibition of erythropoietin stimulated erythropoiesis by pro-inflammatory cytokines, excess erythropoiesis in polycythemia vera associated with the somatic JAK2V617F mutation is accompanied by chronic inflammation. These observations exemplify that erythropoietin independent mechanisms contribute to erythropoiesis which will be further investigated.